This competitive renewal of R01 AG029362 in postmenopausal women parallels the focus of ongoing R37 AG019695 (Actions of Testosterone on the Aging Male GH Axis). In postmenopausal women, sentinel questions are the roles of residual endogenous ovarian and adrenal-derived estrogen in GH regulation, and the hypothalamo-pituitary mechanisms by which estradiol (E2) regulates GH production. The roles of endogenous E2 in GH regulation will be investigated using a unique sex-steroid clamp paradigm designed to inhibit E2 synthesis from androgen precursors, and block tissue actions of E2 via ER. The mechanisms of E2 action will be studied using novel peptide-selective clamp paradigms created to unmask interacting peptide-mediated pathways that jointly (in ensemble) regulate pulsatile GH secretion. Pulsatile GH secretion accounts for >85% of total daily GH production. Prominent species differences in E2 action make clinical investigations essential for mechanistic understanding. The increased difficulty level of clinical studies in turn requires the application of more powerful analytical technology. Accordingly, the present renewal combines all three of (1) innovative sex-steroid clamps;(2) informative peptide-specific GH-pathway clamps;and (3) compelling new analytical methods to dissect ensemble-level (multipathway) mechanisms forcing the decline of pulsatile GH secretion in postmenopausal individuals. The significance of impoverished GH secretion in aging women and men is the increased risk of intra-abdominal obesity, insulin resistance, dyslipidemia, cardiovascular mortality, sarcopenia, osteopenia and physical frailty associated with the low-GH state: Prevention or remediation of these risks is central to maintaining the health of older U.S. citizens. The goal thereby is to promote the development of new non-steroidal and non-peptidyl means to forestall age-related decrements in GH and IGF-I drive to anabolism.
Although postmenopausal age diminishes and estrogen stimulates GH secretion, the mechanisms by which age and estrogen exert their effects remain unknown. The present studies introduce new clinical paradigms and newer technologies to resolve both issues. The expectation is to foster novel ways to limit age-related frailty in women without using estrogen per se.
|Norman, Catalina; Rollene, Nanette; Weist, Suanne M et al. (2014) Short-term estradiol supplementation potentiates low-dose ghrelin action in the presence of GHRH or somatostatin in older women. J Clin Endocrinol Metab 99:E73-80|
|Veldhuis, Johannes D; Dyer, Roy B; Trushin, Sergey A et al. (2014) Immunologic and mass-spectrometric estimates of SHBG concentrations in healthy women. Metabolism 63:783-92|
|Norman, Catalina; Rollene, Nanette L; Erickson, Dana et al. (2014) Estradiol regulates GH-releasing peptide's interactions with GH-releasing hormone and somatostatin in postmenopausal women. Eur J Endocrinol 170:121-9|
|Roelfsema, Ferdinand; Pereira, Alberto M; Biermasz, Nienke R et al. (2014) Hormone secretion by pituitary adenomas is characterized by increased disorderliness and spikiness but more regular pulsing. J Clin Endocrinol Metab 99:3836-44|
|Veldhuis, Johannes D (2013) Changes in pituitary function with ageing and implications for patient care. Nat Rev Endocrinol 9:205-15|
|Veldhuis, Johannes D; Erickson, Dana; Wigham, Jean et al. (2011) Gender, sex-steroid, and secretagogue-selective recovery from growth hormone-induced feedback in older women and men. J Clin Endocrinol Metab 96:2540-7|
|Veldhuis, Johannes D; Roelfsema, Ferdinand; Keenan, Daniel M et al. (2011) Gender, age, body mass index, and IGF-I individually and jointly determine distinct GH dynamics: analyses in one hundred healthy adults. J Clin Endocrinol Metab 96:115-21|
|Veldhuis, Johannes D; Bowers, Cyril Y (2011) Regulated recovery of pulsatile growth hormone secretion from negative feedback: a preclinical investigation. Am J Physiol Regul Integr Comp Physiol 301:R1143-52|
|Veldhuis, Johannes D; Erickson, Dana; Miles, John M et al. (2011) Complex regulation of GH autofeedback under dual-peptide drive: studies under a pharmacological GH and sex steroid clamp. Am J Physiol Endocrinol Metab 300:E1158-65|
|Veldhuis, Johannes D; Keenan, Daniel M; Pincus, Steven M (2010) Regulation of complex pulsatile and rhythmic neuroendocrine systems: the male gonadal axis as a prototype. Prog Brain Res 181:79-110|
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